N-alkylated ketomorphinans are important pharmaceuticals, typically used as analgesics, opiate agonists, and antagonists. With the increasing use of these agents, a practical and effective method of preparation of these compounds is vital to synthesizing diverse N-alkyl substituted ketomorphinans.
N-alkylated ketomorphinans may be prepared using a reductive alkylation reaction. In this type of reaction, the free base of the amine is reacted with an aldehyde forming an imine, iminium salt, or Schiff Base. Reduction of the Schiff Base is normally accomplished by the use of a hydride transfer agent. Previous reductive alkylation methodologies, however, require that the ketone be protected prior to reduction of the imine and then de-protected after reductive amination to restore the ketone group.
Conventional reducing reagents for reductive alkylation may include borohydride reagents (e.g., sodium borohydride reagents, sodium cyanoborohydride), boranes, and aluminum hydride reagents (e.g., lithium aluminum hydride). See, for example, A. F. Abdel-Magid, et al., Reductive Amination of Aldehydes and Ketones by Using Sodium Triacetoxyborohydride, Tet. Lett. 31 (39), pp. 5595-98 (1990). These reagents typically need to be used in stoichiometric quantities to achieve complete reduction. Difficulties resulting from this synthetic method include the release of boron or aluminum salts from the product. Improved reductive alkylation procedures have utilized metal catalytic methodology to achieve the reduction. See, for example, WO 2006/035195 (N. Goodwin, et al.). Hydrogen gas in the presence of a transition metal catalyst has also been used to achieve this reduction. Yet even in the most recent methodologies, if carbonyl compounds are present and not protected, the carbonyls have been reduced to alcohols. By way of example, the use of a Noyori catalyst (ruthenium bound by an activating ligand) along with a hydrogen source reduces a 6-keto group to the corresponding alpha-hydroxy-epimer.
Thus, a need remains for a quick and effective synthetic method for the preparation of N-alkylated ketomorphinans resulting in high yields. In particular, a need remains for a process for the preparation of an N-alkylated ketomorphinan while maintaining the ketone group as unprotected. A need also remains for a process for the preparation of an N-alkylated ketomorphinan while maintaining the ketone group as unprotected, wherein the ketone functionality within the ketomorphinan is not substantially reduced.